Giovanna Zinzallas forskning: Interaktion mellan bHLHZip-transkriptionsfaktorer och SWI/SNF-komplex

Forskning om hur transkriptionsfaktorer styr program för genuttryck och cellöde i normala och maligna celler

Description

How the transcriptional machinery orchestrates gene expression programs during development, renewal and in response to environmental signals is one of the outstanding questions in biology. Giovanna Zinzalla and her research team tackle this fundamental problem by focusing on determining at the molecular level the mechanisms regulating the interactions between transcription factors and their interactions with co-factors, especially with epigenetic regulators.

Giovanna Zinzalla's research approaches encompass the use of chemistry, biochemistry, biophysics and structural biology. The ultimate goal is to develop therapeutic agents to treat human diseases, and new approaches for regenerative medicine.

Giovanna Zinzalla's team have been focusing on two key molecular machineries: (1) MYC and other members of its Basic-Helix-Loop-Helix-Zipper (bHLHZip) network of transcription factors; and (2) SWI/SNF (BAF) chromatin remodelling complexes.

They work on determining: how the MYC transcription factor cooperation leads to gene repression; and how the MYC extended network of bHLHLZ transcription factors, i.e., the c- MYC like MONDOA/ChREBP paralogs, regulate metabolism.

Their projects on the SWI/SNF complexes are currently directed to understand: how these chromatin remodelling complexes control MYC gene expression; and how the BAF60 and the BAF155/170 subunits, respectively, mediates interactions with diverse transcription factors with roles in cellular processes, such as regeneration, cardiac development and metabolism. The team ise also exploring ways to target the SWI/SNF complexes for the development of new therapies.

Figure 1. The complex interplay between transcription factors and chromatin remodelling machines: on the left, the crystal structure of the bHLHZip C-terminal domain of human protein c-MYC (in red) bound to its obligatory partner MAX (in blue), and on the right, a schematic representation of the subunits of SWI/SNF complexes. Shared core subunits of the SWI/SNF complexes are in blue. Unique subunits belonging to BAF (SWI/SNF-A), PBAF (SWI/SNF-b), and ncBAF (non-canonical SWI/SNF) complexes are in green, magenta and yellow, respectively. The interplay is mediated by protein-protein interactions and mutual transcriptional regulation to control each other levels of protein expression. Illustration: Giovanna Zinzalla

Selected publications

Biophysical and Structural Methods to Study the bHLHZip Region of Human c-MYC Zinzalla G

Methods in molecular biology (Clifton, N.J.) 2021;2318():21-43

SWI/SNF subunit BAF155 N-terminus structure informs the impact of cancer-associated mutations and reveals a potential drug binding site

Allen MD, Freund S, Bycroft M, Zinzalla G

Commun Biol. 2021 May 5;4(1):528.

Structure of the BRK domain of the SWI/SNF chromatin remodeling complex subunit BRG1 reveals a potential role in protein-protein interactions.

Allen MD, Bycroft M, Zinzalla G

Protein Sci. 2020 Apr;29(4):1047-1053.

Crystal Structures and Nuclear Magnetic Resonance Studies of the Apo Form of the c- MYC:MAX bHLHZip Complex Reveal a Helical Basic Region in the Absence of DNA. Sammak S, Hamdani N, Gorrec F, Allen MD, Freund SMV, Bycroft M, Zinzalla G Biochemistry 2019 07;58(29):3144-3154

The structure of INI1/hSNF5 RPT1 and its interactions with the c-MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex.

Sammak S, Allen MD, Hamdani N, Bycroft M, Zinzalla G

FEBS J. 2018 11;285(22):4165-4180

A selective high afinity MYC-binding compound inhibits MYC:MAX interaction and MYC- dependent tumor cell proliferation.

Castell A, Yan Q, Fawkner K, Hydbring P, Zhang F, Verschut V, Franco M, Zakaria SM, Bazzar W,

Goodwin J, Zinzalla G, Larsson LG

Sci Rep 2018 07;8(1):10064

A New Way Forward in Cancer Drug Discovery: Inhibiting the SWI/SNF Chromatin Remodelling Complex.

Zinzalla G

Chembiochem 2016 Apr;17(8):677-82

Targeting protein-protein interactions (PPIs) of transcription factors: Challenges of intrinsically disordered proteins (IDPs) and regions (IDRs).

Sammak S, Zinzalla G

Prog. Biophys. Mol. Biol. 2015 Oct;119(1):41-6

The SWI/SNF Subunit INI1 Contains an N-Terminal Winged Helix DNA Binding Domain that Is a Target for Mutations in Schwannomatosis.

Allen MD, Freund SM, Zinzalla G, Bycroft M

Structure 2015 Jul;23(7):1344-9

Tetracycline analogues with a selective inhibitory effect on HIF-1alpha

Bendiabdellah Y, Rahman, KM, Uranchimeg B, Nahar KS, Antonow D, Shoemaker R.H., Melillo G, Zinzalla G, Thurston, DE

Med. Chem. Commun., 2014,5, 923-926.

Observation of unphosphorylated STAT3 core protein binding to target dsDNA by PEMSA and X-ray crystallography.

Nkansah E, Shah R, Collie GW, Parkinson GN, Palmer J, Rahman KM, Bui TT, Drake AF, Husby J, Neidle S, Zinzalla G, Thurston DE, Wilderspin AF

FEBS Lett 2013 Apr;587(7):833-9

Small-molecule inhibition of c-MYC:MAX leucine zipper formation is revealed by ion mobility mass spectrometry.

Harvey SR, Porrini M, Stachl C, MacMillan D, Zinzalla G, Barran PE

J. Am. Chem. Soc. 2012 Nov;134(47):19384-92

See full list of publications

Research Collaborations

Prof. Don Ayer, Huntsman Cancer Institute, University of Utah, USA
Dr Mark Bycroft, University of Cambridge, UK
Prof. Gerard Evan, Francis Crick Institute, London, UK
Prof. Laura Itzhaki, University of Cambridge, UK
Prof. Lars-Gunnar Larsson, Karolinska Institutet, Sweden
Prof. Mark Rubin, MD, Bern Center for Precision Medicine (BCPM), University of Bern, Switzerland
Prof. Sophia Yaliraki, Imperial College London, UK

Areas of Expertise

Organic Chemistry
Medicinal Chemistry
Protein Science
Structural Biology
Biochemical and Biophysical Assays
Protein-Protein Interactions
Drug Discovery
Transcription Factors
Chromatin Remodelling Systems

Contact

Giovanna Zinzalla, researcher
Department of Pharmaceutical Biosciences
E-mail: Giovanna.Zinzalla@uu.se

Researcher Bio at Uppsala University